Ethylene-carboxyl copolymers as drug delivery matrices

ABSTRACT

A coated stent is provided including a coating composed of one or more co-polymers of ethylene with carboxylic acid wherein the carboxylic acid co-monomer content is 5-50 wt %.

CROSS REFERENCE

This is a divisional of U.S. patent application Ser. No. 09/748,719filed Dec. 22, 2000, which issued on Nov. 30, 2004 as U.S. Pat. No.6,824,559.

BACKGROUND OF THE INVENTION

The present invention relates to a drug delivery matrix coating, to animplantable device comprising the drug delivery matrix coating, to amethod for making the drug delivery matrix coating and to a method forapplying the drug delivery matrix coating to a stent.

Stents are typically implanted within a vessel in a contracted state andexpanded when in place in the vessel in order to maintain patency of thevessel to allow fluid flow through the vessel. Typically, implantationof such stents is accomplished by mounting the stent on the balloonportion of a catheter, positioning the stent in a body lumen, andexpanding the stent to an expanded state by inflation of a balloonwithin the stent. The stent can then be left in place by deflating theballoon and removing the catheter.

Because of the mechanical strength that is required to properly supportvessel walls, stents are typically constructed of metallic materials.However, it is frequently desirable to provide localized pharmacologicaltreatment of a vessel at the site being supported by the stent. It isconvenient to employ the stent as a vehicle for drug delivery. Themetallic materials are not capable of carrying and releasing drugs.Polymeric materials capable of absorbing and releasing drugs typicallydo not fulfill the structural and mechanical requirements of a stent,especially when the polymeric materials are loaded with a drug, sincedrug loading of a polymeric material diminishes the structural andmechanical properties of the polymeric material. Since it is oftenuseful to provide localized therapeutic pharmacological treatment of avessel at the location being treated with the stent, it is desirable tocombine such polymeric materials with existing stent structures toprovide a stent with the capability of absorbing therapeutic drugs orother agents, for placement and release of the therapeutic agents at aspecific intravascular site.

One solution historically used has been coating a stent's metallicstructure with a polymeric material in order to provide a stent capableof both supporting adequate mechanical loads as well as deliveringdrugs. Techniques typically used to join polymers to metallic stentsinclude dipping, spraying and conforming processes. However, thesetechniques have tended to introduce other problems into the stentproducts. Other problems with drug delivery matrix coatings includemarginal adhesion to a substrate such as a metal substrate, insufficientelongation of the coating resulting in cracks, and limited andsub-optimal solvent choices that result in difficult application of thecoating and poor manufacturability.

SUMMARY OF THE INVENTION

The present invention relates to a copolymer of carboxylic acid in alayer as applied in a drug releasing implant. The carboxylic acidcopolymer may be in a matrix having a drug or in a primer or in adiffusion barrier.

One embodiment of the present invention includes a drug deliverycoating. The drug delivery coating comprises a matrix comprising one ormore co-polymers of ethylene comprising the reaction products ofcarboxylic acid containing unsaturated monomers. The drug deliverycoating also includes a drug contacting the matrix. The drug deliverycoating has a strong adhesion due to Van der Waals interaction resultingfrom carboxylic acid bonding of the coating to the material beingcoated.

One other embodiment of the present invention includes a stent. Thestent comprises a tubular main body. The stent also comprises a coatingthat is adhered to the tubular main body. The coating comprises one ormore co-polymers of ethylene wherein the co-polymers include acarboxylic acid moiety. The carboxylic acid moiety comprises one or moreof acrylic acid, methacrylic acid, maleic acid, itaconic acid and allcombinations and esters of these monomers. The coating deforms to adegree that accommodates stent deformation and, as a result, isresistant to cracking and delamination. The coating adheres to stentscomprised of materials such as stainless steel.

Another embodiment of the present invention includes a drug deliverysystem. The drug delivery system comprises a tubular main body and afirst coating that overlays the tubular main body. A drug isincorporated into the first coating. A coating comprising one or moreco-polymers of ethylene with a carboxylic acid moiety overlays the firstcoating. The carboxylic acid moiety is one or more of acrylic acid,methacrylic acid, maleic acid, itaconic acid and all combinations andesters of these monomers. For some embodiments, the first coating isbiodegradable.

Another embodiment of the present invention includes a method forimproving manufacturability of a drug delivery system used with amedical device. The method comprises providing a medical device with amain body and providing a coating comprising a cross-linkableco-polymers of ethylene with carboxylic acid. The method also includesapplying the coating to the main body of the medical device.

The drug delivery coating of the present invention adheres to a metalsubstrate and has an elongation comparable to a metal or polymericsubstrate. The drug delivery coating is soluble in a ternary blend. Theternary blend eases application of the coating to a medical devicesurface, such as a stent. The ternary blend also improvesmanufacturability as compared to polymeric drug delivery systems notusing the ternary blend.

DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates a perspective view of one embodiment of the stent ofthe present invention.

FIG. 2 illustrates a cross-sectional view of one embodiment of the drugdelivery matrix of the present invention, wherein a drug is positionedwithin a polymeric matrix.

FIG. 3 a illustrates a cross-sectional view of another embodiment of thedrug delivery matrix of the present invention wherein a polymeric matrixoverlays a drug-containing matrix.

FIG. 3 b illustrates a cross-sectional view of another embodiment of thedrug delivery matrix of the present invention wherein the polymericmatrix overlays the drug-containing matrix.

DETAILED DESCRIPTION

One embodiment of the present invention comprises an array of matrixdrug delivery coating 42 usable as drug delivery coatings for stents 40,namely metal stents and polymeric stents, such as are illustrated, inone embodiment, in FIG. 1. While a roll is shown in FIG. 1, it isunderstood that the coating may be a sheath or a thin coat for otherimplant embodiments. The array of matrix coatings comprises one or morecross-linkable co-polymers of ethylene comonomer, —(C₂H₄)— thatcomprises one or more carboxylic acid moieties. The carboxylic acidmoieties are, for some embodiments, unsaturated carboxylic acid monomersor unsaturated carboxylic acid co-monomers. The unsaturated carboxylicacid monomers or unsaturated carboxylic acid co-monomers are one or moreof acrylic acid, methacrylic acid, maleic acid, itaconic acid and allcombinations and esters of these monomers.

The carboxylic acid co-monomer content is at least about 5% by weightand not more than about 50% by weight of the polymer. The carboxylicco-monomer content is, for some embodiments, in a range of about 15 to40% by weight of the polymer. The acid groups are, for some embodiments,partially neutralized. For other embodiments, the acid groups are fullyneutralized using sodium hydroxide, potassium hydroxide, ammonia, andthe like.

The term “ionomers” as used herein refers to polymers with acid groupsthat are neutralized with metal cations.

The term “matrix polymer” as used herein refers to a polymer capable offorming a coating on a surface of a medical apparatus and providing anetwork for containing a drug. The matrix polymer has functionalmoieties capable of crosslinking by hydrogen bonds to other moietieswithin the matrix polymer and crosslinking to any other moieties derivedfrom the medical apparatus to enhance the strength and toughness of thecoating. Adhesion is enhanced by Van der Waals interaction resultingfrom carboxylic acid bonding of the coating to the medical apparatus.

The term “elongation” as used herein refers to a percent elongation tobreak or an amount of strain the polymer can endure before rupturing.

Another embodiment of the present invention includes the matrix drugdelivery coating of the present invention and a drug. For someembodiments, such as is illustrated at 20 in FIG. 2, the polymercomprising the coating acts as a drug eluting matrix. The drug 22 isincorporated within the drug eluting matrix 24. For some embodiments,the drug is a particulate which is dispersed within the drug elutingmatrix 24. For other embodiments, the drug is dissolved within thematrix 24.

The drug delivery coating acts as a barrier to rapid diffusion of thedrug through the coating and to a treatment site. The drug deliverycoating has a thickness ranging from about 0.1 to 3.0 mils, when appliedto a stent. Because diffusion and drug release are delayed by thecoating, the coating is usable for releasing drugs to a treatment siteafter a time interval of no or negligible drug release.

The coating of the present invention is usable with multiple drugdelivery matrices in order to orchestrate drug release. In oneembodiment, the coating, as shown in cross-section in FIG. 2, overlays asurface 26, such as a stent surface. With this embodiment, the coatingfunctions as a drug release coating. For another embodiment which is notshown, the coating is drug free and does not function as a drug releasecoating.

For some embodiments, the coating made with co-polymers of ethylene is aprimer layer or a diffusion barrier. As a primer layer, the coatingadheres to the surface of a stent. The primer layer also has functionalmoieties for crosslinking to a matrix polymer. For some embodiments, theprimer layer is a dispersion of ethylene acrylic acid (EAA), such asPrimacor 5980, available from Dow-Corning Corp. in Midland, Mich. orMICHEMPRIME 4983R, available from Michelman of Cincinnati, Ohio, orwhich is a dispersion that is capable of providing carboxyl moieties tothe surface. As a primer layer, the coating of the present inventiondeforms to a degree that accommodates stent deformation, such as stentstrut deformation. As a result, the coating is resistant to cracking anddelamination and provides both elongation and high adhesion. For someembodiments, a drug is incorporated in the primer or the diffusionbarrier. Typically, the drug concentration for these embodiments islower if the matrix layer is present.

Thus, the coating of the present invention accomplishes what many otherpolymers cannot perform. Thermosets such as epoxies, polyesters,phenolics, polyimide, as well as conventional thermoplastics such asvinyl chloride, cellulosics, styrene, methyl methacrylate andthermoplastics such as PEEK, PPS, polysulfone, polycarbonate, Mylar,unless the strain occurs above the polymer's glass transitiontemperature, do not elongate and adhere to a degree that makes themacceptable coatings for stent devices.

For other embodiments, the polymer comprising the coating is positionedto provide a diffusion limiting barrier for a drug reservoir, such as amicro-depot 17, shown in FIG. 3 a. The micro-depot 17 is defined by adivot formed at the surface 14 of the stent 13. This embodiment isillustrated generally at 10 in FIG. 3 a. A coating illustrated at 12overlays a stent surface 14. For some embodiments, the coating 12includes drugs and for other embodiments, the coating 12 is drug-free.The polymer overcoat 16 of the present invention overlays the coating12. The coating matrix includes one or more of poly(ethylene-acrylicacid), EAA, poly(ethylene-vinyl alcohol), poly(ethylene vinyl acetate),poly n-butyl methacrylate, poly(ethylene oxide) or a polyurethaneelastomer such as Bionate 80A, manufactured by Polymer Technology Groupof Berkeley, Calif. Bionate 80 is a polycarbonate-urethane and is athermoplastic elastomer formed as a reaction product of a hydroxylterminated polycarbonate, an aromatic diisocyanate, and a low molecularweight glycol which is used as a chain extender. The overcoat 16includes one or more of EAA, ethylene-methacrylic acid (EMAA), and otherethylene, acrylic acid-based materials.

For other embodiments such as is illustrated at 30 in FIG. 3 b, thepolymer overcoat 16 functions as a cover over a drug-only layer 32 or adrug/non-drug mixture layer, which is not shown. The coat may bebiodegradable but there may be non-biodegradable coats, as well. Onelayer of this type is a layer that comprises a drug and a biodegradablematerial such as phosphatidylcholine. Other suitable biodegradablematerials include linear aliphatic polyesters like polyglycolide andpolylactide from poly(alpha-hydroxyacetic acids), poly(orthoesters),polyanhydrides, polysaccharides, poly(ester amides), tyrosine-basedpolyarylates or polyiminocarbonates or polycarbonates,poly(D,L-lactide-urethane), poly(beta-hydroxybutyrate),poly(e-caprolactone), poly[bis(carboxylatophenoxy) phosphazene],poly(amino acids), pseudo-poly(amino acids), and copolymers derived fromamino acids and non-amino acids. As the biodegradable layer degrades,the drug is released.

For other embodiments, the matrix polymer coats a medical device such asa stent as shown at 40 in FIG. 1 but the polymer acts as a primer, andis free of drugs. For these embodiments, the matrix polymer 42 coatssurfaces that are regarded as difficult to coat, such as stainlesssteel. Stainless steel is regarded as a difficult to coat metal becausestainless steel has an outer surface that is trivalent chromium oxide,which provides a less reactive surface than other metal oxides. It isthe interactions between metal oxides on the substrate and functionalgroups on the polymer that provide the adhesive force.

For some embodiments, the polymer coating formulation of the presentinvention also includes one or more of a surfactant, a colorant, and oneor more plasticizers or mixtures of these materials. Some of theco-polymer coating embodiments of the present invention compriseco-polymers that are soluble in ternary blends comprising toluene, achlorinated solvent, and a lower alcohol. The ternary blends of toluene,chlorinated solvents, and lower alcohols, are usable to dissolve and toapply the polymer or polymer/drug blend to a stent. For example, a blendof 15% trichloroethane, 15% 2-propanol and 70% toluene is usable todissolve a coating polymer manufactured by Dow Chemical, PRIMACOR 5980.For some embodiments, the polymer coating formulation is dissolved at anelevated temperature. The use of these ternary blends renders thecoating application process easier in that a coating has a viscositythat eases application and uniformity of thickness.

Specifically, solvents dissolve the polymer to make a coating solution.Surfactants are added to improve substrate wetting. Surfactants are alsoadded to prevent foaming. Plasticizers increase elongation at theexpense of hardness and tensile strength.

The co-polymers are neutralized in a volatile or a non-volatile base.The copolymers are dispersed in water and in co-solvents such as theternary blends that are described. Specifically, the co-solvents includethe ternary blends of toluene, chlorinated solvents and lower alcohols.

In one particular example, a coating of the present invention is madewith a PRIMACOR 5980I, which is manufactured by Dow Chemical of Midland,Mich. The PRIMACOR 5980I is an ethylene acrylic acid copolymer, EAA,that adheres to metals and other polar substrates. The PRIMACOR 5980Ihas the physical properties described in Table 1.

TABLE 1 Physical Properties Test Method Values (SI) Resin PropertiesWeight Percent Comonomer Dow Method 20.5 Melt Index, g/10 min ASTM D1238 300 Melt Flow Rate, g/10 min ASTM D 1238 13.8 Density, g/cc ASTM D792 0.958 DSC Melting Point, F. (C.) Dow Method  171 (77) VicatSoftening Point, F. (C.) ASTM D 1525  108 (42) Molded Part PropertiesUltimate Tensile, psi (Mpa) ASTM D 638 1400 (10) Ultimate Elongation, %ASTM D 638 390 Tensile Modulus, 2% secant, psi(MPa) ASTM D 638 4800 (33)Hardness, Shore D ASTM D 2240 50

One other polymer formulation usable in the coating formulation of thepresent invention is provided in an ammonia neutralized aqueousdispersion at 25% solids, manufactured by Michelman Inc. The productname is Michem Prime 4983R. The Michem Prime 4983R product includes EAAsolids in a percent of 25% non-volatiles. Dow Primacor 5980i is alsousable. The specific gravity is 0.98 to 1.00. The particle size is about0.03 micron. The viscosity is about 50 to 400, as measured with a No. 2spindle. The hardness, as measured by ASTM test D-5, is about 54 sd.

This Michem Prime 4983R dispersion is, for some embodiments, blended ina concentration that is less than 40% w/w, and is preferably within arange of 5 to 20% w/w with a co-solvent and, optionally, with a drugcomponent. This dispersion is applied by standard coating applicationtechniques such as spray coating or dipping, at substantially roomtemperature. When used as a primer, an addition of about 20 to 50micrograms of coating material per stent is typically used. As a matrixwith drug, about 50 to 500 micrograms per stent are applied to eachstent. If used as a diffusion limiting barrier coat, a quantity of about50 to 500 micrograms of material are applied to each stent. Once thecoating is applied to a stent, the coating and stent are baked at lowtemperature, 120 degrees to 150 degrees F., for a period of time that issufficient to drive off the solvents and any volatile amine. Coating andheating produces a conformal coating on the device. For someembodiments, the coating is dried at room temperature, rather than beingsubjected to baking.

Another embodiment of the present invention includes a stent or otherimplantable medical device made with the coating of the presentinvention. The medical device comprises a main body comprising amaterial such as stainless steel, nickel, gold, chrome, nickel titaniumalloy, platinum, other metals, silicone, polyethylene, otherpolyolefins, polyesters, other plastics, glass, polyurethane, acetal,polyamide, and polyvinyl chloride. Medical devices include catheters,microcatheters, wires, wound drains and dressings, arteriovenous shunts,gastroenteric tubes, urethral inserts, laparoscopic equipment, pelletsand implants. The medical devices are made for some embodiments withcoating alone. For other embodiments, the medical devices deliver drugsthrough the drug delivery coating.

The drug delivery coating of the present invention substantiallyeliminates problems of marginal substrate adhesion, insufficientelongation resulting in cracks and limited and sub-optimal solventchoices resulting in difficult application and poor manufacturability.The carboxylic acid groups of the ethylene polymer impart a highadhesion to the coating so that the coating strongly adheres to metal.The ethylene content insures sufficient elongation of the coating toaccommodate the strain associated with stent expansion.

An ability to neutralize the acid groups with a volatile or permanentcounter ion provides water dispersibility properties to the coating. Thewater dispersibility is compatible with organic co-solvents such as2-propanol or methyl ethyl ketone to aid in substrate wetting andimproved application properties. The acid groups that are not ionicallyneutralized in the dried film are usable to associate with amine groupson a drug, such as Actinomycin D, and to retard its release.

Thus, the drug delivery coating of the present invention resists wetabrasion. The coating remains coherent without cracks despite flexingwhen applied to substantially inert surfaces that are difficult to coat,such as stainless steel. This performance is an improvement over othercoatings which do not display optimal properties when applied tostainless steel.

Due to a high ethylene content, the hydrophobic nature of the dry filmretards the transport of drug molecules, which tend to be functionalizedand have some hydrophilic character.

Examples of such active ingredients include antiproliferative substancesas well as antineoplastic, anti-inflammatory, antiplatelet,anticoagulant, antifibrin, antithrombin, antimitotic, antibiotic,antioxidant, and combinations thereof. A suitable example of anantiproliferative substance includes actinomycin D, or derivatives andanalogs thereof (manufactured by Sigma-Aldrich 1001 West Saint PaulAvenue, Milwaukee, Wis. 53233; or COSMEGEN available from Merck).Synonyms of actinomycin D include actinomycin, actinomycin IV,actinomycin I1, actinomycin X1, and actinomycin C1. Examples of suitableantineoplastics include paclitaxel and docetaxel. Examples of suitableantiplatelets, anticoagulants, antifibrins, and antithrombins includesodium heparin, low molecular weight heparin, hirudin, argatroban,forskolin; vapiprost, prostacyclin arid prostacyclin analogs, dextran,D-phe-pro-arg-chloro-methylketone (synthetic antithrombin),dipyridamole, glycoprotein IIb/IIIa platelet membrane receptorantagonist, recombinant hirudin, thrombin inhibitor (available fromBiogen), and 7E-3B® (an antiplatelet drug from Centocore). Examples ofsuitable antimitotic agents include methotrexate, azathioprine,vincristine, vinblastine, fluorouracil, adriamycin, and mutamycin.Examples of suitable cytostatic or antiproliferative agents includeangiopeptin (a somatostatin analog from Ibsen), angiotensin convertingenzyme inhibitors such as CAPTOPRIL (available from Squibb), CILAZAPRIL(available from Hoffman-LaRoche), or LISINOPRIL (available from Merck);calcium channel blockers (such as Nifedipine), colchicine, fibroblastgrowth factor (FGF) antagonists, fish oil (omega 3-fatty acid),histamine antagonist, LOVASTATIN (an inhibitor of HMG-CoA reductase, acholesterol lowering drug from Merck), monoclonal antibodies (such asPDGF receptors), nitroprusside, phosphodiesterase inhibitors,prostaglandin inhibitor (available form Glazo), Seramin (a PDGFantagonist), serotonin blockers, steroids, thioprotease inhibitors,triazolopyrimidine (a PDGF antagonist), and nitric oxide. Othertherapeutic substances or agents which may be appropriate includealpha-interferon, genetically engineered epithelial cells, anddexamethasone.

While the foregoing therapeutic agents have been used to prevent ortreat restenosis, the drugs are provided by way of example and are notmeant to be limiting, since other therapeutic drugs may be developedwhich are equally applicable for use in the present invention. Thetreatment of diseases using the therapeutic agents described as well asdosage rates are known.

For some embodiments, a selected drug is intimately mixed with thepolymeric coating material of the present invention in order touniformly disperse the therapeutic drug in the polymeric material. Forother embodiments, the drug is incorporated into a matrix such as abiodegradable polymer matrix. The specific method of uniformlydispersing the therapeutic drug in the polymer is variable, and dependsupon the stability of the therapeutic drug to thermal processing.Ethylene and acrylic acid, for example, are co-polymerized by freeradical techniques to form an essentially linear polymer. However,ethylene is not “crosslinked” by the acid co-polymer. The acid groupsrandomly placed along the chain hydrogen bond to each other. The acidgroups crosslink each other, not the ethylene groups.

For some embodiments, the therapeutic drug is uniformly dispersed in thepolymeric material by coextruding small solid particles of the drug withthe polymer material. The specific method of uniformly dispersing thetherapeutic drug in the polymer varies and depends upon the stability ofthe therapeutic drug to thermal processing. The therapeutic drug isuniformly dispersed in the polymeric material by coextruding small solidparticles of the selected therapeutic drug with the selected polymericmaterial. This extrusion device includes a hopper into which thepolymeric material and small particles of selected therapeutic drug areadded together, and into which a porosigen is also added, if desired.The extruder also typically includes a lead screw that drives and thatintimately mixes the ingredients together, to uniformly disperse thesmall particles of the therapeutic drug, and if desired, a porosigen aswell, in the polymeric material.

The barrel of the extruder is heated by temperature controlled heaterssurrounding the barrel in stagers. A motor and associated gears areprovided to drive the lead screw, and a cooling system is also typicallyprovided. This method of intimately mixing the therapeutic drug andpolymeric material yields a relatively high and uniformly distributedloading of the therapeutic drug in the polymer. While a loading of thetherapeutic drug is currently no more than about 40% by weight,depending upon the specific application and interaction of the polymerwith the drug, drug loadings as high as 70% by weight have been achievedby this method. A preferable concentration range is 5 to 20% by weight.The drug loaded polymer is extrudible into an appropriate shape, or canbe subsequently calendered to produce a drug loaded polymer film havinga smooth surface, with the therapeutic drug uniformly distributed in thefilm.

A polycarbonate-urethane material such as Bionate 80 is veryhygroscopic. Pellets of Bionate 80 are dried by a process, such as witha forced air dehumidifying dryer at 82 degrees C for at least about 4hours prior to extrusion or injection molding. Bionate 80 pellets aretypically filtered during extrusion through filters such as a 350 meshfilter and two 500 mesh filters.

Extrusion equipment is set with a cross head temperature of about 200degrees C to 215 degrees C to initiate the flow. Once flow isestablished, the cross head temperature is decreased until steady,viscous flow is achieved. Extrusion conditions for thepolycarbonate-urethane material are typically within the followingranges:

Conditions Temperature (C.) Temperature (F.) Barrel-Zone 1 200-215390-420 Barrel-Zone 2 193-230 380-445 Barrel-Zone 3 193-230 380-445 Die200-215 390-420 Melt Temperature 191-221 375-430 Extruder ConfigurationParameter Value Length to Diameter Ratio 24:1 Compression Ratio 2.5:1 to3.5:1 Cooling Water Temperature 18-20 degrees C.

The particles of the desired therapeutic drug are formed to have amaximum cross-sectional dimension of about 10 microns. An averageparticle size of less than 10 microns and a uniform distribution of theparticles of the therapeutic drug in the polymeric material provide atherapeutically effective amount of the therapeutic drug in the layer ofthe polymeric material to be applied to the structure of the stent,since the layer of polymeric material typically is as thin as 25microns. The size and distribution of the particles of the therapeuticdrug affect the physical properties of the polymer.

In other embodiments, the therapeutic drug is compounded with thepolymer by calendering the ingredients, such as in a two roll mill, forexample. This method yields a relatively high and uniformly distributedloading of the therapeutic drug in the polymer.

The matrix coating is applicable to the surface of a stent using methodssuch as dipping, spraying, flowing, rolling and brushing. Thickness ofthe coating ranges from about 0.1 to about 3 mils. The thickness isadjustable by adjusting viscosity of the coating material prior toapplication. Thickness is also adjustable by applying multiple coatinglayers.

The embodiments illustrated and discussed in this specification areintended only to teach those skilled in the art the best way known tothe inventors to make and use the invention. Nothing in thisspecification should be considered as limiting the scope of the presentinvention. Modifications and variations of the above-describedembodiments of the invention are possible without departing from theinvention, as appreciated by those skilled in the art in light of theabove teachings. It is therefore to be understood that, within the scopeof the claims and their equivalents, the invention may be practiced,otherwise than as specifically described.

1. A method of coating an implantable medical device, comprising: addinga copolymer of an ethylene comonomer with a carboxylic acid comonmer toa solvent system to form a composition; mixing a therapeutic drug withthe copolymer composition to allow the drug uniformly dispersed in thecopolymer composition, wherein the drug concentration is 5% to 20% byweight; applying the composition to an implantable medical device; andallowing the solvent system to evaporate; wherein the carboxylic acidcomonomer content is 5%-50 wt %.
 2. The method of claim 1, wherein thecarboxylic acid comonomer is selected from a group consisting of acrylicacid, methacrylic acid, maleic acid, itaconic acid, and esters thereof.3. The method of claim 1, wherein adding the copolymer to the solventsystem further comprises neutralizing the copolymer in a volatile or anon-volatile base and dispersing the copolymer in water and/or aco-solvent.
 4. The method of claim 1, wherein the solvent systemcomprises toluene.
 5. The method of claim 4, wherein the solvent systemfurther comprises a chlorinated solvent and a lower alcohol.
 6. Themethod of claim 1, wherein the carboxylic acid co-monomer has a contentin the copolymer 15% to 40% by weight.
 7. The method of claim 1, whereinthe co-polymer is ethylene acrylic acid.
 8. The method of claim 1,wherein the device comprises a stent.